Nicotine Chewing Gum Nicotine

฀nicotine฀chewing฀gum฀over฀the฀patch฀is฀that฀its฀dosage฀can฀be฀adjusted฀individually฀over฀ the฀course฀of฀a฀day฀in฀response฀to฀any฀cravings฀that฀may฀be฀experienced.

11.1.3 Nicotine Patch

Nicotine฀ patches฀ were฀ developed฀ as฀ transdermal฀ delivery฀ systems฀ to฀ ensure฀ constant฀ release฀of฀the฀active฀ingredient฀over฀a฀period฀of฀16–24฀h.฀These฀systems฀should฀be฀applied฀ to฀a฀dry฀area฀of฀hairless฀skin,฀and฀the฀application฀site฀should฀be฀varied฀daily.฀Nicorette ® ฀ patches฀are฀available฀in฀strengths฀of฀15,฀10฀and฀5฀mg.฀The฀15-mg฀patch฀contains฀25฀mg฀ nicotine.฀The฀Nicorette฀patch฀is฀intended฀to฀be฀worn฀for฀only฀16฀h,฀i.e.฀not฀during฀the฀night฀ Figs.฀ 11.2 ฀and฀ 11.3 . By฀contrast,฀NiQuitin ® ฀and฀Nicotinell ® ฀aim฀to฀administer฀nicotine฀over฀a฀24฀h฀period.฀ The฀three฀patch฀strengths฀of฀NiQuitin ® ฀and฀Nicotinell ® ฀deliver฀7,฀14฀and฀21฀mg฀nicotine฀to฀ the฀body฀every฀24฀h.฀Thanks฀to฀the฀special฀pharmaceutical฀formulation฀of฀NiQuitin ® ฀incor- porating฀a฀membrane฀type฀that฀releases฀nicotine฀for฀transcutaneous฀delivery,฀they฀contain฀ 36,฀78฀and฀114฀mg฀nicotine฀on฀patch฀areas฀of฀7,฀15฀and฀22฀cm 2 ฀respectively.฀Nicotinell ® ฀ contains฀52.5฀mg฀nicotine฀on฀an฀area฀of฀30฀cm 2 .฀During฀the฀irst฀2฀h฀after฀patch฀application,฀ differences฀have฀been฀detected฀in฀terms฀of฀body฀area฀selected฀chest฀฀leg฀฀back฀฀gluteal฀ region.฀One฀other฀study฀comparing฀absorbtion฀from฀hip฀and฀arm฀did฀not฀ind฀any฀differ- ence.฀The฀observed฀differences฀between฀application฀sites฀are฀without฀clinical฀relevance. Nicotine฀attains฀maximum฀concentrations฀between฀4฀and฀10฀h฀following฀single฀applica- tion,฀and฀levels฀then฀plateau฀over฀16–24฀h.฀Signiicant฀differences฀exist฀between฀the฀area฀ under฀the฀curve฀AUC฀values฀and฀the฀mean฀plasma฀concentration฀curve฀between฀single฀ dose฀and฀steady฀state฀for฀the฀24-h฀patches.฀The฀16-h฀patch฀has฀similar฀plasma฀concentra- tions฀during฀steady฀state฀as฀after฀a฀single฀dose,฀as฀the฀plasma฀level฀decline฀over฀night.฀ Separate฀investigations฀have฀established฀that฀nicotine฀is฀not฀inactivated฀metabolised฀dur- ing฀ transdermal฀ passage,฀ whereas฀ minimal฀ metabolism฀ to฀ the฀ analogous฀ N-oxide฀ or฀ N-methyl฀compounds฀has฀been฀demonstrated฀under฀in฀vitro฀conditions฀following฀6฀day฀incu- bation฀ [39,฀40] .฀Overall,฀the฀metabolism฀of฀nicotine฀to฀cotinine฀during฀transdermal฀passage฀ is฀estimated฀to฀be฀minimal. Nicotine฀release฀from฀patches฀has฀also฀been฀studied฀in฀terms฀of฀differences฀due฀to฀gen- der,฀age฀and฀obesity.฀While฀gender฀and฀age฀differences฀have฀been฀excluded,฀a฀correlation฀ with฀body฀weight฀has฀been฀conirmed,฀with฀AUC฀declining฀as฀body฀weight฀increases฀ [41] .฀ However,฀it฀was฀immaterial฀whether฀the฀patches฀were฀applied฀to฀the฀upper฀arm฀or฀upper฀ body.฀These฀investigations฀did฀not฀reveal฀any฀consequences฀for฀therapy. Plasma฀nicotine฀concentrations฀rise฀if฀cigarettes฀are฀smoked฀in฀addition฀to฀patch฀appli- cation฀see฀Fig.฀ 11.4 .฀Naturally,฀nicotine฀absorption฀from฀cigarettes฀is฀subject฀to฀numerous฀ inluences฀already฀discussed,฀even฀where฀the฀smoker฀is฀required฀to฀smoke฀one฀cigarette฀at฀ 30฀min฀intervals฀over฀a฀15฀h฀experimental฀period฀ [42,฀43] .฀Mean฀nicotine฀concentrations฀at฀ all฀time฀points฀are฀almost฀doubled.฀Mean฀concentrations฀of฀approximately฀40฀ngml฀day฀3฀ and฀50฀ngml฀day฀7฀are฀achieved฀with฀the฀patch฀+฀smoking฀combination,฀whereas฀very฀ much฀lower฀concentrations฀30฀ngml฀are฀found฀with฀an฀ad฀libitum฀smoking฀option.฀In฀ practice,฀however,฀the฀differences฀in฀measured฀plasma฀nicotine฀concentrations฀are฀of฀minor฀ importance฀because฀external฀factors฀determine฀the฀smoker’s฀daily฀cigarette฀consumption.฀ Furthermore,฀experience฀shows฀that฀cigarette฀consumption฀is฀reduced฀when฀nicotine฀prod- ucts฀are฀administered฀concurrently฀because฀the฀accustomed฀nicotine฀concentrations฀are฀ achieved฀by฀smoking฀fewer฀cigarettes.

11.1.4 Nicotine Sublingual Tablet

Two฀studies฀one฀of฀which฀has฀been฀published฀ [10] ฀have฀been฀conducted฀to฀date฀with฀ nicotine฀sublingual฀tablets,฀a฀formulation฀that฀is฀intended฀particularly฀for฀smokers฀who฀ want฀to฀give฀up฀smoking฀but฀who฀do฀not฀like฀chewing฀gum฀ [10] .฀Approximately฀50฀of฀ absorption฀from฀the฀2-mg฀tablet฀occurs฀through฀the฀buccal฀mucosa,฀but฀the฀tablet฀should฀be฀ left฀under฀the฀tongue.฀The฀plasma฀nicotine฀proiles฀were฀similar฀following฀repeated฀admin- istration฀of฀the฀2-mg฀tablet฀and฀a฀2-mg฀gum฀although฀absorption฀of฀nicotine฀from฀the฀2-mg฀ tablet฀at฀higher฀doses฀2฀or฀3฀tablets฀was฀non-linear฀ [44] .

11.1.5 Nicotine Nasal Spray

Nicotine฀nasal฀spray฀is฀the฀formulation฀that฀allows฀the฀most฀rapid฀absorption฀of฀active฀ ingredient฀through฀the฀nasal฀mucosa,฀thus฀enabling฀cravings฀to฀be฀relieved฀more฀effec- tively฀than฀with฀chewing฀gum.฀The฀nasal฀spray฀is฀a฀formulation฀that฀is฀commonly฀associ- ated฀with฀adverse฀effects฀see฀Sect.฀ 11.1.9 .฀Four฀published฀studies฀with฀nicotine฀nasal฀ spray฀alone฀ [8,฀45–47] ฀and฀one฀study฀describing฀the฀combined฀application฀of฀nicotine฀nasal฀ spray฀+฀patch฀ [30] ฀conirm฀its฀high฀level฀of฀eficacy฀Table฀ 11.1 . 10 20 30 40 50 60 70 Nicotine-Plasma Level [ngml] 4 8 12 [h] Fig. 11.4 ฀฀฀Mean฀plasma฀ nicotine฀concentrations฀ following฀2-day฀therapy฀ with฀a฀21-mg฀nicotine฀patch฀ without฀open฀circle฀and฀ with฀additional฀cigarette฀ consumption฀at฀30-min฀ intervals฀open฀triangle฀ n฀=฀14฀under฀experimental฀ conditions.฀Vertical฀bars฀ represent฀the฀standard฀ deviations฀of฀the฀mean฀ see฀ [42]